Functional analysis of epigenetic factors that inhibit cellular senescence

• Project/Area Number: 15K15068
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Kumamoto University
• Principal Investigator: Nakao Mitsuyoshi 熊本大学, 発生医学研究所, 教授 (00217663)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 細胞老化 / エピゲノム / 遺伝子 / 代謝

Outline of Final Research Achievements

Gene regulation and epigenomic conversion are involved in the program of cellular senescence, but the molecular mechanisms remain unclear. We investigated the key processes of cellular senescence, using specific siRNAs libraries against nuclear and chromatin factors, and found that 1) retinoblastoma protein promotes oxidative phosphorylation through up-regulation of glycolytic genes in oncogene-induced senescent cells; 2) the SETD8/PR-Set7 methyltransferase functions as a barrier to prevent senescence-associated metabolic remodeling.

Research Products

• [Int'l Joint Research] ケンブリッジ大学/Imperial College, London(英国)
• [Int'l Joint Research] 国立衛生学研究所NIH(米国)
• [Int'l Joint Research] Leicester大学/Imperial College, London(英国)
• [Int'l Joint Research] Cologne大学(ドイツ)
• [Int'l Joint Research] 国立衛生学研究所(米国)
• [Int'l Joint Research] Ningbo大学(中国)
• [Journal Article] The SETD8/PR-Set7 Methyltransferase Functions as a Barrier to Prevent Senescence-Associated Metabolic Remodeling. (2017)
  • Author(s): Tanaka, H., Takebayashi S. I., Sakamoto, A., Igata, T., Nakatsu, Y., Saitoh, N., Hino, S., and Nakao, M.
  • Journal Title: Cell Rep. Volume: 18 Issue: 9 Pages: 2148-2161
  • DOI: 10.1016/j.celrep.2017.02.021
  • Peer Reviewed / Open Access
• [Journal Article] Potential neuroprotective effects of an LSD1 inhibitor in retinal ganglion cells via p38 MAPK-gamma activity (2016)
  • Author(s): T. Tsutsumi, K. Iwao, H. Hayashi, T. Kawaji, T. Inoue, S. Hino, M. Nakao, and H. Tanihara.
  • Journal Title: Invest. Ophthalmol. Vis. Sci. Volume: 57 Issue: 14 Pages: 6461-6473
  • DOI: 10.1167/iovs.16-19494
  • Peer Reviewed / Open Access
• [Journal Article] Roles of long non-coding RNAs in chromosome domains (2016)
  • Author(s): Tomita, S., Abdalla, M. O. A., Fujiwara, S., Yamamoto, T., Iwase, H., Nakao, M. and Saitoh, N.*.
  • Journal Title: WIREs RNA Volume: - Issue: 2 Pages: 30366-30374
  • DOI: 10.1002/wrna.1384
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Histone demethylase LSD1 controls the phenotypic plasticity of cancer cells (2016)
  • Author(s): S. Hino, K. Kohrogi, and M. Nakao.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 9 Pages: 1187-1192
  • DOI: 10.1111/cas.13004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lysine-specific demethylase-1 contributes to malignant behavior by regulation of invasive activity and metabolic shift in esophageal cancer (2016)
  • Author(s): Kosumi K, Baba Y, Sakamoto Y, Ishimoto T, Harada K, Nakamura K, Kurashige J, Hiyoshi Y, Iwatsuki M, Iwagami S, Sakamoto Y, Miyamoto Y, Yoshida N, Oki E, Watanabe M, Hino S, Nakao M, Baba H
  • Journal Title: Int J Cancer Volume: 138 Issue: 2 Pages: 428-39
  • DOI: 10.1002/ijc.29714
  • Peer Reviewed / Open Access
• [Journal Article] HMGA2 promotes adipogenesis by activating C/EBPβ-mediated expression of PPARγ (2016)
  • Author(s): Y. Xi, W. Shen, L. Ma, M. Zhao, J. Zheng, S. Bu, S. Hino, and M. Nakao.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 472 Issue: 4 Pages: 617-623
  • DOI: 10.1016/j.bbrc.2016.03.015
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The retrovirus HTLV-1 inserts an ectopic CTCF-binding site into the human genome (2016)
  • Author(s): Satou Y, Miyazato P, Ishihara K, Yaguchi H, Melamed A, Miura M, Fukuda A, Nosaka K, Watanabe T, Rowan A, Nakao M, and Bangham CRM.
  • Journal Title: PNAS Volume: in press Issue: 11 Pages: 3054-3059
  • DOI: 10.1073/pnas.1423199113
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Retinoblastoma protein promotes oxidative phosphorylation through up-regulation of glycolytic genes in oncogene-induced senescent cells (2015)
  • Author(s): S. Takebayashi, H. Tanaka, S. Hino, Y. Nakatsu, T. Igata, A. Sakamoto, M. Narita, and M. Nakao.
  • Journal Title: Aging Cell Volume: 14 Issue: 4 Pages: 689-697
  • DOI: 10.1111/acel.12351
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Lysine demethylase LSD1 coordinates glycolytic and mitochondrial metabolism in hepatocellular carcinoma cells. (2015)
  • Author(s): Sakamoto A, Hino S, Nagaoka K, Anan K, Takase R, Matsumori H, Ojima H, Kanai Y, Arita K, Nakao M
  • Journal Title: Cancer Research Volume: 75(7) Issue: 7 Pages: 1445-1456
  • DOI: 10.1158/0008-5472.can-14-1560
  • Peer Reviewed / Open Access
• [Journal Article] A cluster of non-coding RNAs activates the ESR1 locus during breast cancer adaptation to hormone deprivation (2015)
  • Author(s): S. Tomita, M.O. Abdalla, S. Fujiwara, H. Matsumori, K. Maehara, Y. Ohkawa, H. Iwase, N. Saitoh, and M. Nakao.
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 6966-6966
  • DOI: 10.1038/ncomms7966
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The actin family protein ARP6 contributes to the structure and the function of the nucleolus (2015)
  • Author(s): Kitamura, H., Matsumori, H., Kalendova, A., Hozak, P., Goldberg, I.G., Nakao, M., Saitoh, N., Harata, M
  • Journal Title: BBRC Volume: 464 Issue: 2 Pages: 554-560
  • DOI: 10.1016/j.bbrc.2015.07.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] あなたと私はどうして違う？ 体質と遺伝子のサイエンス (2017)
  • Author(s): 中尾光善
  • Organizer: 日本成人病予防協会第42回健康学習セミナー
  • Place of Presentation: 熊本大学、熊本市
  • Invited
• [Presentation] エピジェネティクスと現代人の体質学 (2016)
  • Author(s): 中尾光善
  • Organizer: 第56回リンパ網内系学会総会・第26回日本樹状細胞研究会
  • Place of Presentation: ホテル日航熊本、熊本市
  • Invited
• [Presentation] 細胞老化に関わるエピゲノム因子の探索と解析 (2016)
  • Author(s): 中尾光善
  • Organizer: 第43回日本毒性学会学術年会
  • Place of Presentation: ウインクあいち、名古屋市
  • Invited
• [Presentation] エネルギー代謝とエピジェネティクス (2016)
  • Author(s): 中尾光善
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都国際会議場、京都市
  • Invited
• [Presentation] エピジェネティクスとエネルギー代謝 (2016)
  • Author(s): 中尾光善
  • Organizer: 第10回日本エピジェネティクス研究会年会
  • Place of Presentation: 千里ライフサイエンスセンター、大阪市
  • Invited
• [Presentation] Epigenetic reprogramming in physiology and cancer (2015)
  • Author(s): M. Nakao
  • Organizer: The 6th Hiroshima Conference and 50th Anniversary Commemoration
  • Place of Presentation: 広島国際会議場、広島市
  • Year and Date: 2015-10-24
  • Int'l Joint Research / Invited
• [Presentation] 環境エピゲノムによるエネルギー代謝調節と病態 (2015)
  • Author(s): 中尾光善
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル、東京
  • Year and Date: 2015-10-15
  • Invited
• [Presentation] A cluster of non-coding RNAs, Eleanors, activate the ESR1 locus in therapy-resistant breast cancer cells (2015)
  • Author(s): M. Nakao and N. Saitoh
  • Organizer: The 40th Naito Conference on Epigenetics-From histone code to therapeutic strategy
  • Place of Presentation: CHÂTERAISÉ Gateaux Kingdom SAPPORO, 札幌市
  • Year and Date: 2015-09-17
  • Int'l Joint Research / Invited
• [Presentation] エピジェネティクス：生命のプログラムを解く (2015)
  • Author(s): 中尾光善
  • Organizer: 第13回日本プロテオーム学会JHUPO2015年大会
  • Place of Presentation: くまもと森都心プラザ、熊本市
  • Year and Date: 2015-07-24
  • Invited
• [Presentation] エピジェネティクス機構による代謝制御と病態 (2015)
  • Author(s): 中尾光善、坂元顕久、長岡克弥、日野信次朗
  • Organizer: 第88回日本内分泌学会学術集会
  • Place of Presentation: ホテルニューオータニ東京、東京
  • Year and Date: 2015-04-25
  • Invited
• [Book] 実験医学増刊（遺伝子制御の新たな主役 栄養シグナル）（分担執筆） (2016)
  • Author(s): 日野信次朗、阿南浩太郎、高瀬隆太、興梠健作、中尾光善
  • Total Pages: 230
  • Publisher: 羊土社
• [Book] Bio Clinica（エピゲノムの遺伝）（分担執筆） (2016)
  • Author(s): 興梠健作、日野信次朗、中尾光善
  • Total Pages: 114
  • Publisher: 北隆館
• [Book] あなたと私はどうして違う？ 体質と遺伝子のサイエンス－99.9％同じ設計図から個性と病気が生じる秘密 (2015)
  • Author(s): 中尾光善
  • Total Pages: 221
  • Publisher: 羊土社
• [Book] ドライシンドロームの基礎と臨床（分担執筆） (2015)
  • Author(s): 中元雅史、森山雅文、石原 宏、中尾光善
  • Total Pages: 201
  • Publisher: メディカルレビュー社
• [Remarks] 熊本大学発生医学研究所
  • URL: http://www.imeg.kumamoto-u.ac.jp
• [Patent(Industrial Property Rights)] 神経変性疾患治療剤 (2016)
  • Inventor(s): 谷原秀信、岩尾圭一郎、中尾光善、林秀樹、日野信次朗、 堤孝之
  • Industrial Property Rights Holder: 熊本大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-011705
  • Filing Date: 2016-01-25
• [Funded Workshop] International Symposium on Nuclear Structure and Epigenetics (2015)
  • Place of Presentation: 熊本大学発生医学研究所（熊本市）
  • Year and Date: 2015-08-27